The third component of complement (C3) plays a central role in generating the biologically significant effects of the complement system. Activation of C3 creates cleavage products (C3a and C3b) capable of opsonic and anaphylatoxic activities. In addition, the larger cleavage product, C3b, forms part of the enzymes which activate C5. Thus, C3 is also important in the production of activities mediated by C5-9. The identification of animals and humans with genetically determined deficiencies of individual components of complement has been valuable in generating knowledge about the biology, biochemistry, and genetics of the complement system. Although a few humans with genetically determined C3 deficiency have been described, until recently, no experimental animals with this deficiency had been identified. While inbreeding a colony of dogs for the study of Hereditary Canine Spinal Muscular Atrophy (HCSMA) a number of the dogs were found to have a genetically determined deficiency of C3. The following studies will be performed in order to investigate the basis for the C3 deficiency and define its biochemical and biological characteristics and consequences. The studies will focus on the following seven specific aims: 1) to determine the biochemical and biological characteristics of C3 deficiency in the dog, 2) to purify and characterize the C3 in normal canine sera, 3) to purify and characterize the "C3-like" activity present in the serum of C3 deficient dogs, 4) to determine whether C3 deficient dogs are capable of synthesizing C3 in vitro, 5) to determine the clinical significance of C3 deficiency in the dog, 6) to establish a colony of C3 deficient dogs which is free of Hereditary Canine Spinal Muscular Atrophy, and 7) to develop a functional assay for C3 using serum from C3 deficient dogs. The C3 deficient dog, as the only experimental animal with a genetically determined deficiency of C3, will provide unique opportunities to investigate the role of C3 in a wide variety of immunologic reactions, both in vitro and in vivo. In addition, these animals should also eventually provide valuable insight into the mechanism(s) by which C3 is synthesized and the genetic basis for C3 deficiency.